Clinical impact of TP53 alterations in adrenocortical carcinomas.

ABSTRACT

BACKGROUND: To evaluate the role of somatic TP53 mutations and to correlate somatic and germline mutations with results of immunostaining, a large cohort of ACC patients was analyzed. PATIENTS AND METHODS: Patients with ACC who underwent potential curative surgery at the authors' department were screened for TP53 somatic and germline mutations in exons 5, 6, 7, 8, and 10 by DHPLC analysis. Aberrant samples were further analyzed by direct sequencing. Immunostaining was performed on corresponding paraffin sections in all patients. Complete clinical and follow-up data were correlated with the status of TP53. RESULTS: Thirty ACC patients were included. Four of 30 patients showed aberrant DHPLC configuration and direct sequencing confirmed 2 (7%) germline mutations (R337H, R248W), 1 (3%) somatic mutation (R213X), and 1 (3%) noncoding polymorphism (g.17708 A>T). The only patient with a positive family history harbored a TP53 mutation. Tumors of the three patients with mutations showed aberrant p53 expression in more than 10% of cells by immunostaining, compared to only 3 of 27 patients without mutations (p = 0.009). Aberrant p53 expression (>5%) was detected in 12/30 (40%) ACCs. The latter was associated with an increased Ki67 and van Slooten index (p ≤ 0.001; p = 0.020). Disease-free survival decreased significantly in patients with aberrant p53 IHC of more than 5% of cells (65.7 ± 12.4 vs. 26.6 ± 8.7 months; p = 0.043 log rank test). CONCLUSIONS: Patients with ACC revealed aberrant expression of p53 in 40%, and mutations were identified in 25% of these patients. Therefore aberrant p53 expression should be considered an indicator for genetic testing. A subgroup of apparently sporadic ACC is caused by TP53 germline mutations, and family history is a strong indicator for p53 germline mutations.